Postarrest Steroid Use May Improve Outcomes
of Cardiac Arrest Survivors
Min-Shan Tsai, MD, PhD1,2; Po-Ya Chuang, MHA3; Chien-Hua Huang, MD, PhD1; Chao-Hsiun Tang, PhD3;
Ping-Hsun Yu, MD4; Wei-Tien Chang, MD, PhD1; Wen-Jone Chen, MD, PhD1,5
Objectives: To evaluate the ramifications of steroid use during
postarrest care.
Design: Retrospective observational population-based study
enrolled patients during years 2004–2011 with 1-year follow-up.
Setting: Taiwan National Health Insurance Research Database.
Patients: Adult nontraumatic cardiac arrest patients in the emer-
gency department, who survived to admission.
Interventions: These patients were classified into the steroid and
nonsteroid groups based on whether steroid was used or not dur-
ing hospitalization. A propensity score was used to match patient
underlying characteristics, steroid use prior to cardiac arrest, the
vasopressors, and shockable rhythm during cardiopulmonary
resuscitation, hospital level, and socioeconomic status.
Measurements and Main Results: There were 5,445 patients in
each group after propensity score matching. A total of 4,119
patients (75.65%) in the steroid group died during hospitaliza-
tion, as compared with 4,403 patients (80.86%) in the nonste-
roid group (adjusted hazard ratio, 0.74; 95% CI, 0.70–0.77;
p < 0.0001). The mortality rate at 1 year was significantly lower
1
Department of Emergency Medicine, National Taiwan University Medical
College and Hospital, Taipei, Taiwan.
2
Department of Emergency Medicine, National Taiwan University Hospital
Hsin-Chu Branch, Hsinchu, Taiwan.
3
School of Health Care Administration, Taipei Medical University, Taipei,
Taiwan.
4
Department of Emergency Medicine, Taipei Hospital, Ministry of Health
and Welfare, Taipei, Taiwan.
5
Division of Cardiology, Department of Internal Medicine, National Taiwan
University Medical College and Hospital, Taipei, Taiwan.
This study was performed in National University Hospital.
Supplemental digital content is available for this article. Direct URL cita-
tions appear in the printed text and are provided in the HTML and PDF
versions of this article on the journal’s website (http://journals.lww.com/
ccmjournal).
Supported, in part, by a research grant from the National Taiwan University
Hospital, grant number 104-S2755.
Dr. Chuang received funding from National Taiwan University Hospital.
The remaining authors have disclosed that they do not have any potential
conflicts of interest.
For information regarding this article, E-mail: wjchen1955@ntu.edu.tw
Copyright © 2018 by the Society of Critical Care Medicine and Wolters
Kluwer Health, Inc. All Rights Reserved.
DOI: 10.1097/CCM.0000000000003468
Critical Care Medicine
Copyright © 2018 by the Society of Critical Care Medicine and Wolters Kluwer Health, Inc. All Rights Reserved.
in the steroid group than in the nonsteroid group (83.54% vs
87.77%; adjusted hazard ratio, 0.73; 95% CI, 0.70–0.76; p <
0.0001). Steroid use during hospitalization was associated with
survival to discharge, regardless of age, gender, underlying dis-
eases (diabetes mellitus, chronic obstructive pulmonary disease,
asthma), shockable rhythm, and steroid use prior to cardiac arrest.
Conclusions: In this retrospective observational study, postarrest
steroid use was associated with better survival to hospital dis-
charge and 1-year survival. (Crit Care Med 2018; XX:00–00)
Key Words: cardiac arrest; propensity score; steroid; survival;
Taiwan National Health Insurance Research Database
C
ardiac arrest is a rapidly lethal condition and associated
with a high mortality rate, even after successful resusci-
tation. Following the return of spontaneous circulation
(ROSC), postcardiac arrest syndrome, a complex combination
of pathophysiologic processes that involve cerebral injury,
myocardial dysfunction, systemic ischemia-reperfusion injury,
and inflammatory response accounts for most hemodynamic
instability and mortality during the postcardiac arrest period.
Postcardiac arrest syndrome shares many features with severe
sepsis and multiple organ failures such as increased cytokine
production and release, endotoxinemia (1, 2), coagulation
abnormality (3, 4), and adrenal dysfunction (5, 6).
Several studies have shown that relative adrenal insuffi-
ciency is common during the postcardiac arrest period (5–9),
and may cause impaired vasoregulation and reduced effec-
tiveness of vasopressors, and thus result in postresuscitation
shock (5, 6). Schultz et al (5) reported that circulating cortisol
levels in patients with out-of-hospital cardiac arrest (OHCA)
were lower than those in patients with other stress conditions.
Furthermore, a low serum cortisol level was associated with
unstable hemodynamics after ROSC and short-term survival
(24 hr). Hékimian et al (6) also reported that OHCA survivors
with refractory shock and early mortality had lower cortisol
levels than those who died later. Additionally, relative adrenal
insufficiency has been reported to be a prognostic factor for
early death (within 7 d after admission) and in-hospital mor-
tality (7–9). In two randomized controlled trials conducted by
www.ccmjournal.org 1
Tsai et al
Mentzelopoulos et al (10, 11), patients who received vasopres-
sin, epinephrine, and methylprednisolone during cardiopul-
monary resuscitation (CPR) and stress-dose hydrocortisone
during postcardiac arrest shock displayed a higher frequency
of ROSC, better hemodynamic stability, less organ dysfunc-
tion, and a better rate of survival to hospital discharge with a
favorable neurologic status when compared with patients who
received epinephrine alone. However, because multiple inter-
ventions were used simultaneously, it was difficult to clarify
which of the interventions were truly beneficial. Furthermore,
it was difficult to discern the isolated effect of glucocorticoid
use during postcardiac arrest care on the outcomes, because
the ROSC rates in the study groups were significantly differ-
ent. Conversely, several other studies do not support the use of
glucocorticoids during the postcardiac arrest period, because
those drugs did not significantly improve survival or neuro-
logic outcomes (12–14).
The benefit of steroid supplement during CPR has been
documented in several animal and human studies (15–17).
In the current study, we hypothesized that steroid use during
the postcardiac arrest period may be associated with improved
patient outcomes. Therefore, we analyzed data from the Taiwan
National Health Insurance Research Database (NHIRD) to
determine potential associations between post-ROSC expo-
sure to steroids and critical cardiac arrest outcomes.
METHODS
Study Design and Data Sources
This nationwide retrospective cohort study on the effect of post-
cardiac arrest steroid use was conducted by analyzing health
insurance administrative data retrieved from the Taiwan NHIRD
for the interval of January 1, 2003, to December 31, 2012. The
claims database, which was released by the National Health
Research Institute (NHRI) for research purposes, provides com-
prehensive information on healthcare utilization and demo-
graphics (birthdate, gender, insurance status, area of residence,
dates of services provided, primary and minor diagnostic codes,
primary and minor procedural codes, and itemized expenditures
for each medical service rendered) for greater than 99% of the
entire Taiwanese population of 23 million people (18). The study
protocol was approved by the NHRI and Review Board of the
National Taiwan University Hospital, and the need for informed
consent was waived. All data were deidentified, and confidenti-
ality assurances were addressed in accordance with data regula-
tions of the National Health Insurance (NHI) Administration.
Study Subjects
Our database search identified 174,068 patients who had under-
gone CPR (procedure code: 47029C) in the emergency depart-
ment between January 1, 2004, and December 31, 2011. Among
those patients, 172,016 received subsequent medical care and
were identified as possible candidates for our study. Patients
who were less than 18 years old or older at date of presentation
(n = 4,041) and those involved in trauma (n = 12,698) were
excluded. To identify patients in cardiac arrest during acute
2 www.ccmjournal.org
Copyright © 2018 by the Society of Critical Care Medicine and Wolters Kluwer Health, Inc. All Rights Reserved.
hospital care,patients not triaged as level 1 (resuscitation/emergent)
(n = 2,436), and patients with an emergency department obser-
vation time greater than 6 hours (n = 7,197) were also excluded.
After identifying 22,768 nontraumatic adult cardiac arrest sur-
vivors, we further excluded patients who received steroid during
CPR (n = 1,180), patients who received steroid for greater than 1
month after ROSC (n = 2,398), and patients given prednisolone
equivalent dose greater than 1,250 mg/d (equal to methylpred-
nisolone dose of 1 g/d as pulse therapy) (n = 23). This left 19,229
patients available for inclusion in our study (the first sample).
Based on whether the patient received steroid during hospitaliza-
tion, the 19,229 patients were then divided into the steroid group
(n = 5,477) and nonsteroid group (n = 13,752). Among the first
sample, 6,955 patients with a history of steroid use within 1 year
(oral, IV, and intraarticular administration of steroid) prior to
cardiac arrest were further selected as the secondary sample (ste-
roid group, n = 2,227; nonsteroid group, n = 4,728). A total of
12,274 patients without a history of steroid within 1 year prior
to cardiac arrest constituted the third sample (steroid group,
n = 3,250; nonsteroid group, n = 9,024) (Fig. 1).
Definition of Variables
The primary study outcome was defined as survival to discharge,
and the secondary outcome was 1-year survival. A death event
was identified if the discharge status of index admission was
“death,” the patient had a death record in the catastrophic illness
registry, or the patient was disenrolled from the NHI program.
The main focus of the study was the effect of steroid use during
hospitalization following cardiac arrest, and the relevant infor-
mation was collected from claims data generated by hospital care.
The type and quantity of administered steroid during the entire
hospitalization after ROSC were obtained from the NHIRD. The
allowable steroidal supplements were hydrocortisone, meth-
ylprednisolone, prednisolone, triamcinolone, dexamethasone,
and betamethasone. The controlled variables were age, gender,
presenting complaint, shockable rhythm, epinephrine dosage,
total shocks delivered during CPR, and cardiac catheteriza-
tion. The presenting complaint was recognized from the Inter-
national Classification of Diseases, 9th Edition code of primary
diagnosis at admission. The steroid and nonsteroid groups had
two patients with missing urbanization level of residence and
geographic distribution, respectively. They were excluded from
analysis of propensity score (PS). To clarify whether the steroid
dose was associated with outcomes, we attempted to standard-
ize the prednisolone equivalent dose (prednisolone equivalent
dose/d), which was calculated as the total dose of prednisolone
equivalent given during hospitalization (when hospitalization
duration was < 1 mo) or the first month (when hospitalization
duration was ≥ 1 mo), divided by the corresponding number of
days (either hospitalization duration or 30 d). We then further
divided the steroid group into four different strata using quar-
tiles of standardized prednisolone equivalent dose.
Computation and Matching of PS
Propensity scoring was used to reduce selection bias between the
steroid and nonsteroid groups. The PS, defined as the probability
XXX 2018 • Volume XX • Number XXX
 Clinical Investigation

variables and frequencies and

percentages for categorical
variables. The standardized
difference as effect size was
calculated to compare group
differences and assess the bal-
ance of the baseline character-
istic of study subjects before
and after PS matching (21).
The impact of steroid use and
the steroid dose on survival to
discharge and 1-year survival
was determined by the Cox
proportional hazard model.
A bootstrapping approach by
resampling for 100 replica-
tions with replacement from
the original samples was used
to perform internal model
validation in assessing survival
to discharge (22).The adjusted
1-year survival curves were
also plotted via the Cox pro-
portional hazard model. When
performing the dose analysis, a
receiver operating characteris-
tic (ROC) curve was plotted to
determine the optimal steroid
dose cut-off value. Subgroup
analyses were performed to
examine relationships between
steroid use, clinical charac-
Figure 1. Process of selecting the study subjects. CPR = cardiopulmonary resuscitation, ED = emergency teristics, and survival to dis-
department. charge. All computations were
performed using standard
of receiving steroid, was first estimated by modeling a logistic software (SAS/Stat v9.3 for Windows; SAS Institute, Cary, NC).
regression drawn from pertinent characteristics (19). The Hosmer- The components of retrospective review were checked by using
Lemeshow goodness-of-fit test was then used to assess propensity the Strengthening the Reporting of Observational Studies in
models’ performance. Results of the logistic regression model used Epidemiology checklist for a cohort study (Supplemental
for PS matching are presented in Supplemental Table 1 (Supple- Table 4, Supplemental Digital Content 4, http://links.lww.com/
mental Digital Content 1, http://links.lww.com/CCM/E67), Sup- CCM/E70).
plemental Table 2 (Supplemental Digital Content 2, http://links.
lww.com/CCM/E68), and Supplemental Table 3 (Supplemental RESULTS
Digital Content 3, http://links.lww.com/CCM/E69). The underlying characteristics, CPR events, and socioeconomic
The steroid and nonsteroid groups were matched by PS using status of the enrolled patients are shown in Table 1. When
8 to 1 digit-based greedy matching algorithm with the nearest compared with patients in the nonsteroid group, a higher per-
available pair matching method at 1:1 ratio (cases:controls) centage of patients in the steroid group had chronic obstruc-
without replacement, as proposed by Parsons (20). The final tive pulmonary disease (COPD), asthma, adrenal insufficiency,
PS-matched sample consisted of 5,445 patients in each group autoimmune disease, steroid use within 1 year prior to cardiac
among total patients, 2,188 patients among patients with prior arrest, and were treated in a tertiary medical center. In contrast,
steroid use, and 3,248 patients among patients without prior lower percentages of patients in the steroid group had coro-
steroid use, respectively. nary artery disease (CAD) chronic kidney disease (CKD), a low
frequency of shockable rhythm, and required only a smaller
Statistical Analyses dose of epinephrine. After matching with the PS, there were
The demographic and clinical characteristics of study sub- 5,445 patients in the steroid and nonsteroid groups, respec-
jects were summarized using the mean ± sd for continuous tively. Supplemental Table 5 (Supplemental Digital Content

Critical Care Medicine www.ccmjournal.org 3

Copyright © 2018 by the Society of Critical Care Medicine and Wolters Kluwer Health, Inc. All Rights Reserved.
Tsai et al

TABLE 1. Baseline Characteristics Between Steroid and Nonsteroid Groups

Before Propensity Score Matching After Propensity Score Matching

Steroid, Nonsteroid, Steroid, Nonsteroid,

n = 5,477, n = 13,752, Standardized n = 5,445, n = 5,445, Standardized
Baseline Characteristics n (%) n (%) Difference n (%) n (%) Difference

Age, yr, mean ± sd 67.91 ± 16.26 68.14 ± 16.41 0.014 67.92 ± 16.27 67.78 ± 16.55 0.009
Gender, male 3,243 (59.21) 8,094 (58.86) 0.007 3,223 (59.19) 3,240 (59.5) 0.006
Presenting complaint 0.099
Cardiac event 1,077 (19.66) 2,655 (19.31) 1,070 (19.65) 1,067 (19.6)
Respiratory event 696 (12.71) 1,337 (9.72) 686 (12.6) 711 (13.06) 0.014
Other event 1,180 (21.54) 3,034 (22.06) 1,176 (21.6) 1,175 (21.58)
Unknown 2,524 (46.08) 6,726 (48.91) 2,513 (46.15) 2,492 (45.77)
Diabetes mellitus 1,732 (31.62) 4,409 (32.06) 0.009 1,721 (31.61) 1,711 (31.42) 0.004
Hypertension 2,608 (47.62) 6,623 (48.16) 0.011 2,589 (47.55) 2,575 (47.29) 0.005
Coronary artery disease 1,034 (18.88) 2,865 (20.83) 0.049 1,030 (18.92) 1,050 (19.28) 0.009
Heart failure 745 (13.6) 1,973 (14.35) 0.021 740 (13.59) 743 (13.65) 0.002
Atrial fibrillation 287 (5.24) 778 (5.66) 0.018 287 (5.27) 281 (5.16) 0.005
Chronic kidney disease 580 (10.59) 1,623 (11.8) 0.038 579 (10.63) 567 (10.41) 0.007
Malignancy 565 (10.32) 1,509 (10.97) 0.021 558 (10.25) 529 (9.72) 0.018
Chronic obstructive lung 1,040 (18.99) 2,047 (14.89) 0.110 1,024 (18.81) 1,032 (18.95) 0.004
disease
Asthma 425 (7.76) 660 (4.8) 0.122 408 (7.49) 406 (7.46) 0.001
Adrenal insufficiency 43 (0.79) 53 (0.39) 0.052 38 (0.7) 35 (0.64) 0.007
Autoimmune disease 104 (1.9) 136 (0.99) 0.076 96 (1.76) 94 (1.73) 0.003
Steroid use prior to cardiac 2,227 (40.66) 4,728 (34.38) 0.130 2,195 (40.31) 2,166 (39.78) 0.011
arrest (1 yr)
Shockable rhythm 1,346 (24.58) 3,782 (27.5) 0.067 1,341 (24.63) 1,338 (24.57) 0.001
Epinephrine dosage, mg, 5.67 ± 5.26 6.44 ± 6.23 0.133 5.68 ± 5.27 5.72 ± 5.23 0.007
mean ± sd
Vasopressin 20 (0.37) 28 (0.2) 0.030 19 (0.35) 22 (0.4) 0.009
Tertiary medical center 1,649 (30.11) 3,613 (26.27) 0.085 1,640 (30.12) 1,621 (29.77) 0.008
Urbanization level of residence 0.080
1 (high) 1,433 (26.17) 3,390 (24.65) 1,425 (26.17) 1,439 (26.43)
2 2,308 (42.16) 6,235 (45.35) 2,301 (42.26) 2,270 (41.69)
0.013
3 477 (8.71) 1,295 (9.42) 474 (8.71) 471 (8.65)
≥ 4 (low) 1,257 (22.96) 2,830 (20.58) 1,245 (22.87) 1,265 (23.23)
Missing 2 2
Geographic distribution 0.160
Taipei 1,999 (36.51) 5,242 (38.12) 1,993 (36.6) 1,993 (36.6)
Northern 701 (12.8) 2,086 (15.17) 699 (12.84) 731 (13.43)
Central 1,530 (27.95) 3,598 (26.17) 1,523 (27.97) 1,482 (27.22)
0.025
Southern 568 (10.37) 911 (6.63) 555 (10.19) 553 (10.16)
Kaopin 429 (7.84) 1,126 (8.19) 427 (7.84) 445 (8.17)
Eastern 248 (4.53) 787 (5.72) 248 (4.55) 241 (4.43)
Missing 2 2
Standardized difference equals to difference in means or proportions divided by se; imbalance defined as absolute value greater than 0.10 (small effect size).

4 www.ccmjournal.org XXX 2018 • Volume XX • Number XXX

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 Clinical Investigation

TABLE 2. Outcomes Between the Steroid and Nonsteroid Groups

Before Propensity Score Matching After Propensity Score Matching

Steroid Nonsteroid HR Adjusted Steroid Nonsteroid HR Adjusted

Outcomes Death, n (%) Death, n (%) (95% CI) HR (95% CI) Death, n (%) Death, n (%) (95% CI) HR (95% CI)

Total patients n = 5,477 n = 13,752 n = 5,445 n = 5,445

Survival to 4,143 11,354 0.73 0.74 4,119 4,403 0.75 0.74
discharge (75.64) (82.56) (0.70–0.76)a (0.71–0.77)a (75.65) (80.86) (0.72–0.79)a (0.70–0.77)a
One-yr survival 4,575 12,270 0.73 0.73 4,549 4,779 0.76 0.73
(83.53) (89.22) (0.71–0.75)a (0.71–0.76)a (83.54) (87.77) (0.73–0.79)a (0.70–0.76)a
Patients with n = 2,227 n = 4,728 n = 2,188 n = 2,188
steroid use prior
to cardiac arrest
Survival to 1,723 3,945 0.75 0.76 1,694 1,787 0.80 0.76
discharge (77.37) (83.44) (0.71–0.79)a (0.72–0.81)a (77.42) (81.67) (0.74–0.85)a (0.71–0.82)b
One-yr survival 1,914 4,303 0.73 0.74 1,882 1,957 0.78 0.74
(85.95) (91.01) (0.69–0.71)a (0.70–0.78)a (86.01) (89.44) (0.73–0.83)a (0.69–0.79)a
Patients without n = 3,250 n = 9,024 n = 3,248 n = 3,248
steroid use prior
to cardiac arrest
Survival to 2,420 7,409 0.71 0.73 2,420 2,630 0.73 0.72
discharge (74.46) (82.1) (0.68–0.75)a (0.69–0.76)a (74.51) (80.97) (0.69–0.77)a (0.68–0.77)a
One-yr survival 2,661 7,967 0.72 0.73 2,661 2,832 0.75 0.73
(81.88) (88.29) (0.69–0.76)a (0.69–0.76)a (81.93) (87.19) (0.71–0.79)a (0.69–0.77)a
HR = hazard ratio.
p < 0.0001.
a

Adjusted for age, cardiac catheterization, epinephrine dose, gender, presenting complaint, shock number, shockable rhythm.

5, http://links.lww.com/CCM/E71) and Supplemental Table 6
(Supplemental Digital Content 6, http://links.lww.com/CCM/
E72) shows demographic and clinical characteristics of the
patients with and without steroid use prior to cardiac arrest,
respectively. After PS matching, no difference existed between
the steroid and nonsteroid groups in the patients with and
without steroid use prior to cardiac arrest, respectively. Base-
line characteristic of unmatched patients in each steroid group
were listed in Supplemental Table 7 (Supplemental Digital
Content 7, http://links.lww.com/CCM/E73).
Among all the samples (total patients, patients with and
without prior steroid use before cardiac arrest), steroid use
during hospitalization benefitted the following endpoints:
survival to discharge and 1-year survival in both unmatched
and matched cohorts (Table 2). With 100 bootstrap replica-
tions, the optimism-corrected area under the ROC curve
ranged from 0.77 to 0.80 for models with either steroid use
or steroid dose as a predictor, showing the models have good
performance. The adjusted 1-year survival curves shown in
Figure 2 showed significant difference between the two groups
in total matched patients (adjusted hazard ratio, 0.73; 95%
CI, 0.70–0.76; p < 0.0001). We next investigated whether the
steroid use during hospitalization may have interacted with
individual clinical characteristics to affect the survival to dis-
charge. As shown in Supplemental Figure 1 (Supplemental
Digital Content 8, http://links.lww.com/CCM/E74), steroid
use during hospitalization was associated with better survival
to discharge, regardless of age, gender, underlying diseases
(diabetes, COPD, asthma), shockable rhythm, and steroid use
within 1 year prior to cardiac arrest.
The outcomes of patients in each quartile with consecutive
increases in steroid dose are listed in Table 3. The demographic
and clinical characteristics of each quartile of the total patients,
patients with and without steroid use prior to cardiac arrest are
shown in Supplemental Table 8 (Supplemental Digital Content
9, http://links.lww.com/CCM/E75), Supplemental Table
9 (Supplemental Digital Content 10, http://links.lww.com/
CCM/E76), and Supplemental Table 10 (Supplemental Digital
Content 11, http://links.lww.com/CCM/E77). Supplemental
Table 11 (Supplemental Digital Content 12, http://links.lww.
com/CCM/E78) demonstrates the duration of hospitaliza-
tion in each steroid strata. The duration of hospitalization
and prednisolone dose equivalent of each quartile were listed
in Supplemental Table 12 (Supplemental Digital Content 13,
http://links.lww.com/CCM/E79). In all the samples, patients
in the first (the lowest dose) and second quartiles benefited
from steroids in terms of survival to discharge and 1-year sur-
vival. However, these benefits began to disappear in the third
quartile and reversed in the fourth quartile (the highest dose).
Therefore, we created a ROC curve of the third quartile which
suggested a steroid dose of 50 mg/d as the optimal cut-off
value (Supplemental Fig. 2, Supplemental Digital Content 14,

Critical Care Medicine www.ccmjournal.org 5

Copyright © 2018 by the Society of Critical Care Medicine and Wolters Kluwer Health, Inc. All Rights Reserved.
Tsai et al

and leukocyte adhesion (28)

and ameliorates endotoxin-
mediated myocardial dys-
function and hemodynamic
instability (29). Furthermore,
glucocorticoids also help to
maintain cardiovascular sta-
bility by inhibiting catechol-
amine reuptake, enhancing
vascular response to vasopres-
sors (11, 30) and decreasing
nitric oxide-mediated vasodi-
lation (31).
However, the question of
whether glucocorticoid use
during the postcardiac arrest
period is beneficial to car-
diac arrest survivors has been
debated for years. Jastremski et
al (12) found that steroid use
Figure 2. The 1-yr survival curves of the groups. There is a significant difference between these groups within 8 hours after ROSC did
(p < 0.0001). not improve survival or neuro-
logic recovery in a retrospec-
tive study. However, that study
http://links.lww.com/CCM/E80). Thus the steroid group was was limited by differences in the etiology of cardiac arrest and
divided into a low steroid group (≤ 50 mg/d) and a high steroid underlying characteristics between the study groups that poten-
group (> 50 mg/d). Supplemental Table 13 (Supplemental tially favored the nonsteroid group. In another nonrandom-
Digital Content 15, http://links.lww.com/CCM/E81) shows ized retrospective study of 458 OHCA survivors, no significant
that the low steroid group was associated with lower mortal- differences in survival or neurologic recovery between patients
ity when compared with the nonsteroid group, and the high with and without steroid use were identified (13). Donnino et
steroid group was associated with worse outcomes. The esti- al (14) conducted a randomized, double-blind, placebo-con-
mations of model internal validity in assessing survival to dis- trolled trial, and found that hydrocortisone did not improve
charge in matched cohorts are shown in Supplemental Table the time to shock reversal or clinical outcomes in patients with
14 (Supplemental Digital Content 16, http://links.lww.com/ refractory shock following cardiac arrest. However, there were
CCM/E82). only 25 patients in each group, and the timing of first steroid
dose was not restricted, which raised the question of whether
DISCUSSION a therapeutic window may exist. In contrast, two prospective,
The current study evaluated the association between steroids randomized, double-blind, placebo-controlled, parallel-group
administered during postcardiac arrest care and the outcomes trials showed that combination therapy with vasopressors and
of cardiac arrest survivors by analyzing data from the NHIRD. methylprednisolone during CPR, followed by hydrocortisone
The NHIRD showed that 22,768 patients had been successfully after ROSC, improved neurologic outcomes, and the rate of
resuscitated from nontraumatic cardiac arrest during acute survival to hospital discharge. As previously mentioned, mul-
hospital care from 2004 to 2011. Our findings demonstrate tiple interventions given at the same time and obvious differ-
that steroid use after ROSC may benefit survival to hospital ences in ROSC rates between patient groups make it difficult
discharge and 1-year survival. To our best knowledge, this to identify the isolated benefit of steroid administration after
study is the first to use nationwide population-based data to ROSC (10, 11). Different from the limitation of small patient
assess the independent association between steroid adminis- numbers and design features in these clinical studies, the cur-
tered during the postcardiac arrest period and the outcomes of rent study investigated the association between postarrest ste-
cardiac arrest survivors. roid use and outcome of cardiac arrest survivors by analyzing
The postcardiac arrest syndrome may profit from glucocor- nationwide population-based data. To avoid the influence of
ticoid administered after ROSC in several aspects in addition steroid use during CPR in the current study, the patients who
to adrenal insufficiency. Glucocorticoids have been reported to received steroid during resuscitation were excluded. Also, the
decrease oxidative stress (23), reduce apoptosis (24), and thus variable “steroid use within 1 year prior to cardiac arrest” was
ameliorate postresuscitation myocardial dysfunction (25) and matched to attenuate potential observational bias generated by
cerebral injury (26). Glucocorticoid administration following steroid dependence prior to cardiac arrest. Furthermore, after
cardiac arrest also attenuates circulating cytokine levels (27) reassessing the effect of postarrest steroid administration in

6 www.ccmjournal.org XXX 2018 • Volume XX • Number XXX

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 Clinical Investigation

TABLE 3. Outcomes Between Dose Levels of Steroid Use Per Day

Adjusted
Steroid Dose Level n Death, n (%) HR (95% CI) p HR (95% CI) p

Total patients
Survival to discharge
  Nonsteroid 5,445 4,403 (80.86) 1 1
   First quartile (0.53–10.66 mg/d) 1,361 637 (46.8) 0.31 (0.28–0.33) < 0.0001 0.32 (0.30–0.35) < 0.0001
   Second quartile (10.71–27.59 mg/d) 1,365 1,073 (78.61) 0.80 (0.75–0.85) < 0.0001 0.77 (0.71–0.81) < 0.0001
   Third quartile (27.63–58.18 mg/d) 1,359 1,170 (86.09) 1.00 (0.94–1.07) 0.9409 0.93 (0.87–0.99) 0.0196
   Fourth quartile (58.33–1,250.00 mg/d) 1,360 1,239 (91.1) 1.34 (1.26–1.43) < 0.0001 1.25 (1.17–1.33) < 0.0001
One-yr survival
  Nonsteroid 5,445 4,779 (87.77) 1 1
   First quartile (0.53–10.66 mg/d) 1,361 823 (60.47) 0.35 (0.33–0.38) < 0.0001 0.37 (0.34–0.40) < 0.0001
   Second quartile (10.71–27.59 mg/d) 1,365 1,182 (86.59) 0.81 (0.76–0.87) < 0.0001 0.75 (0.71–0.80) < 0.0001
   Third quartile (27.63–58.18 mg/d) 1,359 1,251 (92.05) 1.00 (0.94–1.06) 0.9936 0.90 (0.84–0.95) 0.0004
   Fourth quartile (58.33–1,250.00 mg/d) 1,360 1,293 (95.07) 1.28 (1.20–1.36) < 0.0001 1.17 (1.10–1.24) < 0.0001
Patients with steroid use prior to cardiac arrest
Survival to discharge
  Nonsteroid 2,188 1,787 (81.67) 1 1
   First quartile (0.53–10.63 mg/d) 464 230 (49.57) 0.34 (0.29–0.39) < 0.0001 0.35 (0.31–0.40) < 0.0001
   Second quartile (10.71–27.50 mg/d) 547 430 (78.61) 0.80 (0.72–0.89) < 0.0001 0.759 (0.66–0.82) < 0.0001
   Third quartile (27.63–58.18 mg/d) 569 485 (85.24) 0.97 (0.88–1.07) 0.5454 0.90 (0.81–0.99) 0.0356
   Fourth quartile (58.33–1,250.00 mg/d) 608 549 (90.3) 1.31 (1.19–1.45) < 0.0001 1.23 (1.12–1.36) < 0.0001
One-yr survival
  Nonsteroid 2,188 1,957 (89.44) 1 1
   First quartile (0.53–10.66 mg/d) 464 310 (66.81) 0.39 (0.34–0.44) < 0.0001 0.40 (0.35–0.45) < 0.0001
   Second quartile (10.71–27.50 mg/d) 547 472 (86.29) 0.78 (0.71–0.86) < 0.0001 0.72 (0.65–0.79) < 0.0001
   Third quartile (27.63–58.18 mg/d) 569 523 (91.92) 0.94 (0.86–1.04) 0.229 0.86 (0.78–0.94) 0.0015
   Fourth quartile (58.33–1,250.00 mg/d) 608 577 (94.9) 1.22 (1.11–1.33) < 0.0001 1.14 (1.04–1.25) 0.0069
Patients without steroid use prior to cardiac arrest
Survival to discharge
  Nonsteroid 3,248 2,630 (80.97) 1 1
   First quartile (0.82–8.75 mg/d) 811 357 (44.02) 0.28 (0.25–0.32) < 0.0001 0.30 (0.27–0.34) < 0.0001
   Second quartile (8.82–25.00 mg/d) 864 665 (76.97) 0.77 (0.71–0.84) < 0.0001 0.75 (0.69–0.81) < 0.0001
   Third quartile (25.25–51.00 mg/d) 761 655 (86.07) 1.02 (0.94–1.12) 0.5842 0.95 (0.87–1.04) 0.2653
   Fourth quartile (51.04–1,250.00 mg/d) 812 743 (91.5) 1.31 (1.20–1.42) < 0.0001 1.20 (1.10–1.30) < 0.0001
One-yr survival
  Nonsteroid 3,248 2,832 (87.19) 1 1
   First quartile (0.82–8.75 mg/d) 811 449 (55.36) 0.32 (0.29–0.35) < 0.0001 0.34 (0.31–0.38) < 0.0001
   Second quartile (8.82–25.00 mg/d) 864 741 (85.76) 0.806 (0.74–0.87) < 0.0001 0.76 (0.70–0.83) < 0.0001
   Third quartile (25.25–51.00 mg/d) 761 700 (91.98) 1.038 (0.96–1.13) 0.3768 0.94 (0.87–1.02) 0.1611
   Fourth quartile (51.04–1,250.00 mg/d) 812 771 (94.95) 1.284 (1.19–1.39) < 0.0001 1.14 (1.06–1.24) 0.0011
HR = hazard ratio.
Adjusted for age, cardiac catheterization, epinephrine dose, gender, presenting complaint, shock number, shockable rhythm.
a

Critical Care Medicine www.ccmjournal.org 7

Copyright © 2018 by the Society of Critical Care Medicine and Wolters Kluwer Health, Inc. All Rights Reserved.
Tsai et al
patients with and without steroid use prior to cardiac arrest, all
the results showed a consistent benefit of steroids.
In the current study, the dose analysis demonstrated a ben-
efit of steroid administration only on the outcomes of patients
who received a low dose of steroid, and this beneficial effect
was reversed in patients who received a high dose of steroid.
Higher steroid doses were associated with worse outcomes as
compared with the nonsteroid group. Some possible reasons
for this observation are: 1) steroid usage in some patients with
a poor clinical recovery should not be rapidly tapered, 2) some
patients in the high steroid group died too soon to be able
to taper their steroid use, and 3) increasing steroid dose was
associated with decreasing cardiovascular comorbidity burden
(CAD, congestive heart failure, CKD) and increasing pulmo-
nary comorbidity burden (COPD and asthma) potentially
leading to important confounding in this analysis. Further ani-
mal and human studies are required to identify the true effect
of a high steroid dose on outcomes of cardiac arrest survivors.
Our current study has several limitations. First, our analy-
sis of the relationship between patient outcomes and the ste-
roid dose administered is limited by the fact that the NHIRD
provided the data of the total dose of steroid in a period of
hospitalization rather than data on individual doses and their
timing. Also, the reason why postarrest steroid was adminis-
tered was not provided. We attempted to reduce confounding
factors by excluding patients who received steroid greater than
1 month and patients receiving pulse steroid therapy. We also
standardized the dose equivalent with the duration of hospi-
talization. Second, we did not adjust therapeutic hypothermia
in our outcome analysis, because hypothermia was not covered
by the Taiwan NHI system until 2015, and only a few such cases
were reported. Besides, the general quality-improvement mea-
sures may narrow the difference between groups. Therefore,
we attempted to attenuate the potential variance of postcar-
diac arrest care by matching the steroid and nonsteroid groups
for hospital level and the geographic distribution of hospi-
tals. In addition, we also matched epinephrine and shockable
rhythm, two important survival-related variables, to reduce
the potential confounders. Third, individual patient informa-
tion, including body weight, smoking history, witnessed col-
lapse, bystander CPR, cause of cardiac arrest, hemodynamics
during and after CPR, the reason for steroid use, plasma cor-
tisol and adrenocorticotropic hormone concentrations, causes
of death, and neurologic outcomes were not available in the
Taiwan NHIRD. Fourth, the effect of unmeasured confound-
ers cannot be controlled using PS matching, such that causal-
ity cannot be inferred. Finally, the doses and routes of steroids
prior to cardiac arrest were not investigated and worth explor-
ing in the further appropriately designed studies.
CONCLUSIONS
Among adult survivors with nontraumatic cardiac arrest dur-
ing acute hospital care, steroid administration during the post-
cardiac arrest period may ameliorate survival to discharge and
1-year survival.
8 www.ccmjournal.org
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REFERENCES
1. Adrie C, Adib-Conquy M, Laurent I, et al: Successful cardiopulmonary
resuscitation after cardiac arrest as a “sepsis-like” syndrome. Circula-
tion 2002; 106:562–568
2. Adrie C, Laurent I, Monchi M, et al: Postresuscitation disease after
cardiac arrest: A sepsis-like syndrome? Curr Opin Crit Care 2004;
10:208–212
3. Adrie C, Monchi M, Laurent I, et al: Coagulopathy after successful
cardiopulmonary resuscitation following cardiac arrest: Implication
of the protein C anticoagulant pathway. J Am Coll Cardiol 2005;
46:21–28
4. Böttiger BW, Motsch J, Böhrer H, et al: Activation of blood coagula-
tion after cardiac arrest is not balanced adequately by activation of
endogenous fibrinolysis. Circulation 1995; 92:2572–2578
5. Schultz CH, Rivers EP, Feldkamp CS, et al: A characterization of
hypothalamic-pituitary-adrenal axis function during and after human
cardiac arrest. Crit Care Med 1993; 21:1339–1347
6. Hékimian G, Baugnon T, Thuong M, et al: Cortisol levels and adrenal
reserve after successful cardiac arrest resuscitation. Shock 2004;
22:116–119
7. Kim JJ, Lim YS, Shin JH, et al: Relative adrenal insufficiency after
cardiac arrest: Impact on postresuscitation disease outcome. Am J
Emerg Med 2006; 24:684–688
8. Kim JJ HS, Hwang SY, Jung YB, et al: Hormonal responses upon
return of spontaneous circulation after cardiac arrest: A retrospective
cohort study. Crit Care 2011; 15:R53
9. Pene F, Hyvernat H, Mallet V, et al: Prognostic value of relative adrenal
insufficiency after out-of-hospital cardiac arrest. Intensive Care Med
2005; 31:627–633
10. Mentzelopoulos SD, Malachias S, Chamos C, et al: Vasopressin,
steroids, and epinephrine and neurologically favorable survival after
in-hospital cardiac arrest: A randomized clinical trial. JAMA 2013;
310:270–279
11. Mentzelopoulos SD, Zakynthinos SG, Tzoufi M, et al: Vasopressin,
epinephrine, and corticosteroids for in-hospital cardiac arrest. Arch
Intern Med 2009; 169:15–24
12. Jastremski M, Sutton-Tyrrell K, Vaagenes P, et al: Glucocorticoid
treatment does not improve neurological recovery following cardiac
arrest. Brain Resuscitation Clinical Trial I Study Group. JAMA 1989;
262:3427–3430
13. Grafton ST, Longstreth WT Jr: Steroids after cardiac arrest: A retro-
spective study with concurrent, nonrandomized controls. Neurology
1988; 38:1315–1316
14. Donnino MW, Andersen LW, Berg KM, et al; Collaborating Authors
from the Beth Israel Deaconess Medical Center’s Center for Resusci-
tation Science Research Group: Corticosteroid therapy in refractory
shock following cardiac arrest: A randomized, double-blind, placebo-
controlled, trial. Crit Care 2016; 20:82
15. Tsai MS, Chuang PY, Yu PH, et al: Glucocorticoid use during car-
diopulmonary resuscitation may be beneficial for cardiac arrest. Int J
Cardiol 2016; 222:629–635
16. Smithline H, Rivers E, Appleton T, et al: Corticosteroid supple-
mentation during cardiac arrest in rats. Resuscitation 1993; 25:
257–264
17. Tsai MS, Huang CH, Chang WT, et al: The effect of hydrocortisone on
the outcome of out-of-hospital cardiac arrest patients: A pilot study.
Am J Emerg Med 2007; 25:318–325
18. National Health Research Institute: Background of National Health
Insurance Database. Available at: http://www.nhird.nhri.org.tw//en/
index.htm. Accessed October 1, 2018
19. D’Agostino R Jr: Tutorial in Biostatistics. Propensity score methods for
bias reduction in the comparison of a treatment to a non-randomized
control group. Statist Med 1988; 17, 2265–2281
20. Parsons LS: Performing a 1: N Case-Control Match on Propensity
Score. In: 2004 SUGI 29 Proceeding 165-29, Seattle, WA, Ovation
Research Group, 2004
21. Yang D, Dalton JE: A unified approach to measuring the effect size
between two groups using SAS®. Cleveland, OH, SAS Global Forum
2012, Statistics and Data Analysis, 2012
XXX 2018 • Volume XX • Number XXX

22. Steyerberg EW, Harrell FE Jr, Borsboom GJ, et al: Internal vali-
dation of predictive models: Efficiency of some procedures
for logistic regression analysis. J Clin Epidemiol 2001; 54:
774–781
23. Hall ED: Neuroprotective actions of glucocorticoid and nongluco-
corticoid steroids in acute neuronal injury. Cell Mol Neurobiol 1993;
13:415–432
24. Bishopric NH, Andreka P, Slepak T, et al: Molecular mechanisms
of apoptosis in the cardiac myocyte. Curr Opin Pharmacol 2001;
1:141–150
25. Wynsen JC, Preuss KC, Gross GJ, et al: Steroid-induced enhance-
ment of functional recovery of postischemic, reperfused myocardium
in conscious dogs. Am Heart J 1988; 116:915–925
26. Katz L, Vaagenes P, Safar P, et al: Brain enzyme changes as markers
of brain damage in rat cardiac arrest model. Effects of corticosteroid
therapy. Resuscitation 1989; 17:39–53
Critical Care Medicine
Copyright © 2018 by the Society of Critical Care Medicine and Wolters Kluwer Health, Inc. All Rights Reserved.
Clinical Investigation
27. Buttini M, Mir A, Appel K, et al: Lipopolysaccharide induces expression
of tumour necrosis factor alpha in rat brain: Inhibition by methylpred-
nisolone and by rolipram. Br J Pharmacol 1997; 122:1483–1489
28. Simon D, Borradori L, Simon HU: Glucocorticoids in autoimmune bul-
lous diseases: Are neutrophils the key cellular target? J Invest Derma-
tol 2013; 133:2314–2315
29. Söderberg E, Lipcsey M, Sjölin J, et al: Counteraction of early circula-
tory derangement by administration of low dose steroid treatment at
the onset of established endotoxemic shock is not directly mediated
by TNF-α and IL-6. Steroids 2012; 77:1101–1106
30. Oppert M, Schindler R, Husung C, et al: Low-dose hydrocortisone
improves shock reversal and reduces cytokine levels in early hyperdy-
namic septic shock. Crit Care Med 2005; 33:2457–2464
31. Matsumura M, Kakishita H, Suzuki M, et al: Dexamethasone sup-
presses iNOS gene expression by inhibiting NF-kappaB in vascular
smooth muscle cells. Life Sci 2001; 69:1067–1077
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